DOCSLIB.ORG

Identification and Characterization of a Novel Human Testis-Specific

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification and Characterization of a Novel Human Testis-Specific Biochemical and Biophysical Research Communications 285, 400–408 (2001) doi:10.1006/bbrc.2001.5165, available online at http://www.idealibrary.com on Identification and Characterization of a Novel Human Testis-Specific Kinase Substrate Gene Which Is Downregulated in Testicular Tumors Andreas Scorilas,*,† George M. Yousef,*,† Klaus Jung,‡ Ewa Rajpert-De Meyts,§ Stephan Carsten,‡ and Eleftherios P. Diamandis*,†,1 *Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; †Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada; ‡Department of Urology, University Hospital Charite, Humboldt University, Berlin, Germany; and §Department of Growth and Reproduction, Juliane Marie Centre, National University Hospital, Copenhagen, Denmark Received June 8, 2001 physiology, most probably in the process of spermato- By using the positional candidate gene approach, we genesis or spermiogenesis. © 2001 Academic Press identified a novel putative serine/threonine kinase Key Words: kinase substrates; testis-specific genes; substrate gene that maps to chromosome 19q13.3. gene mapping; gene characterization; TSKS; testis- Screening of expressed sequence tags and reverse specific kinase substrate; RRAS; IRF3; testicular transcription–polymerase chain reaction of total RNA cancer. from human tissues allowed us to establish the expres- sion of the gene and delineate its genomic organiza- tion (GenBank Accession No. AF200923). This gene (TSKS, for testis-specific kinase substrate) is com- Protein phosphorylation is the most common post- posed of 11 exons and 10 intervening introns and is translational protein modification in eukaryotes and a likely the human homolog of the mouse testis-specific fundamental mechanism for the direct or indirect con- serine kinase substrate gene. The predicted protein- trol of all cellular processes. Considering the integral coding region of the gene is 1779 bp, encoding for a role that protein kinases play in the control of cellular 592-amino-acid polypeptide with a calculated molecu- mechanisms and signal transduction, it is not surpris- lar mass of 65.1 kDa. Genomic analysis of the region ing that several protein kinases have been shown to be 19q13.3 placed the TSKS gene close to the known genes involved in spermatogenesis (1, 2). Nevertheless, only IRF3, RRAS, and ␣-Adaptin A. TSKS exhibits high lev- a few kinases have been characterized, whose expres- els of expression exclusively in human testicular tis- sion is restricted to either germ cells or to the testis. sue. The expression of TSKS is downregulated in can- The phosphoglycerate kinase-2 and the serine/ cerous testicular tissue, in comparison to adjacent threonine kinase MAK are predominantly expressed in normal tissue. TSKS expression was very low or unde- spermatocytes during meiosis (3). The serine/threonine tectable in seminoma, teratocarcinoma, embryonal, kinase c-MOS and the kinase NEK-1 have been impli- and Leydig cell tumors, while high expression was observed in testicular tissue adjacent to tumors which cated in the control of meiosis in both spermatocytes contain premalignant carcinoma in situ. The expres- and oocytes (4, 5). Mouse studies demonstrate that sion of the TSKS gene was very low in two human spermiogenesis, comprising cytodifferentiation and de- embryonal carcinoma cell lines, 2102Ep and NTERA-2. tachment, involves a complex pattern of interaction These observations suggest a role of TSKS in testicular between members of a novel family of serine/threonine kinases and as yet uncharacterized substrates (2). Abbreviations used: TSKS, testis-specific kinase substrate, IRF3, Other reports describe a possible role of serine/ interferon regulatory factor 3; PSA, prostate-specific antigen; tssk, testis-specific serine kinase; tssks, testis-specific serine kinase sub- threonine kinases and their substrates in the progres- strate; LLNL, Lawrence Livermore National Laboratory; EST, ex- sion of testicular tumors of germ cell origin (6, 7). pressed sequence tag; RT-PCR, reverse transcription–polymerase Recently, Kueng et al. employed the yeast two- chain reaction. hybrid system with testis-specific serine kinase (tssk) 1 1 To whom correspondence and reprint requests should be addressed at Department of Pathology and Laboratory Medicine, Mount Sinai and tssk2 cDNA as baits and a prey cDNA library from Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. mouse testis and isolated a novel cDNA which encoded Fax: (416) 586-8628. E-mail: [email protected]. for a 65-kDa protein, interacting specifically with both 0006-291X/01 $35.00 400 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved. Vol. 285, No. 2, 2001 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS tssk1 and tssk2 (2). This protein was phosphorylated sequences. BLAST homology searching for the proteins encoded by by both kinases (see GenBank Accession No. AF the exons were performed using the BLASTP program and the Gen- 025310). The expression of the interacting clone was Bank databases (12). also testis-specific and paralleled the developmental Structure analysis studies. Multiple alignment was performed us- expression observed for the kinases themselves (2). In ing the Clustal X multiple alignment program (16). Phylogenetic stud- ies were performed using the Phylip software package (17). Distance the same study, tssk2 was found to be the orthologue of matrix analysis was performed using the “Neighbor-Joining/UPGMA” the human DGS-G gene, whose deletion is suspected to program and parsimony analysis was done using the “Protpars” pro- be involved in the pathogenesis of Di George and velo- gram (18). Hydrophobicity study was performed using the Baylor Col- cardiofacial syndromes (8). lege of Medicine search launcher program. Signal peptide and trans- In this report we describe analysis of an area spanning membrane regions were predicted using the SignalP (19) and Tmpred (20) software. Protein structure analysis was performed by SAPS pro- approximately 100 kb of contiguous DNA sequence on gram (21). Sequence analysis tools were utilized to detect the presence human chromosome 19 (19q13.3) for the purpose of iden- of possible sites of posttranslational modification on our putative pro- tifying new genes by the method of positional candidate tein. We used the analysis program PROSITE (22) and NetOGlyc 2.0 cloning (9–11). Our approach allowed us to clone a gene, (23) to detect N- and O-glycosylation, as well as the presence of kinase tentatively named TSKS (for testis-specific kinase sub- phosphorylation motifs. strate; GenBank Accession No. AF200923). This gene is Tissue expression of TSKS. Total RNA isolated from 28 different located closed to RRAS and the human IRF3 gene. On human tissues was purchased from Clontech (Palo Alto, CA). We prepared cDNA as described below and used it for PCRs with the homology analysis, the human TSKS gene was found to primers TSKS-F2 and TSKS-R1, described in Table 2. be similar to the Mus musculus tssk1 and tssk2 substrate Expression of TSKS in testis cancer. Included in this study tissue (tssks) gene, described by Kueng et al. (2). We here de- samples from 15 patients who had undergone radical orchiectomy for scribe the identification of the new gene, its mapping and testicular, tumors at the Charite University Hospital, Germany and its localization, in relation to other genes clustering in the the National University Hospital, Denmark. Patient age ranged same region. In addition, we describe its genomic, mRNA from 23 to 60 years with a median of 36. Matched testicular tissue and protein structure. We further present extensive tis- samples were obtained from the cancerous and non-cancerous parts of the same testis, from 10 of the patients. All patients had a sue expression studies and demonstrate that, in addition histologically-confirmed diagnosis of primary testicular cancer and to testis, which shows the highest expression, the gene is received no treatment before surgery. Of the 10 matched samples, 5 expressed at low levels in prostate, female breast, pla- tumors were seminomas, 3 were categorized as embryonal carcino- centa, ovary, and thymus. Moreover, we examined TSKS mas and 2 were teratocarcinomas. Other tissue samples included one expression in human testicular tumors and teratocar- Leydig cell tumor and two samples of testicular tissue containing pre-malignant carcinoma in situ tubules within morphologically nor- cinoma-derived cell lines and found gene downregulation mal testicular parenchyma. In addition, the expression of the TSKS in comparison to normal testicular tissue. gene was examined in two embryonal carcinoma cell lines derived from a human teratocarcinoma; pluripotet (NTERA-2) and nullipo- tent (2102Ep) (24). The normal and tumor tissues were immediately MATERIALS AND METHODS frozen in liquid nitrogen after surgical resection and stored at Ϫ80°C until extraction. We prepared cDNA as described below and used it Gene mapping. Large DNA sequencing data for chromosome 19 for PCRs with the primers TSKS-F2 and TSKS-R1 (Table 2). Tissue is available at the Lawrence Livermore National Laboratory (LLNL) cDNAs were amplified at a 1:10 dilution. database. We have screened approximately 100 kb of genomic se- Reverse transcription–polymerase chain reaction (RT-PCR). To- quence, encompassing a region on chromosome 19q13.3-13.4, where tal RNA was extracted from the tissues or cell lines using Trizol several cancer-associated
Load more

Recommended publications
  • Nck Adaptor Proteins Link Nephrin at the Podocyte Slit Diaphragm to the Hippo Regulator WTIP
    Nck Adaptor Proteins Link Nephrin at the Podocyte Slit Diaphragm to the Hippo Regulator WTIP by Ava Keyvani Chahi A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Master of Science in Molecular and Cellular Biology Guelph, Ontario, Canada © Ava Keyvani Chahi, December, 2014 ABSTRACT NCK ADAPTOR PROTEINS LINK NEPHRIN AT THE PODOCYTE SLIT DIAPHRAGM TO THE HIPPO REGULATOR WTIP Ava Keyvani Chahi Advisor: University of Guelph, 2014 Dr. Nina Jones Podocytes are specialized epithelial cells that contribute to the kidney blood filtration barrier. Their unique cytoskeletal architecture and other complex biological signals are largely maintained by a modified adherens junction known as the slit diaphragm (SD). A major component of the SD is the transmembrane protein nephrin, which upon tyrosine phosphorylation of the intracellular domain regulates actin remodeling and cell survival. Nck adaptor proteins are a critical component of the filtration barrier and connect nephrin to actin-remodeling proteins by binding phosphotyrosine residues and proline-rich motifs. Herein we identify a novel Nck binding partner, Wilm’s tumor interacting protein (WTIP). WTIP is a transcription regulator in podocytes, though Nck is not nuclear localized under conditions known to induce WTIP nuclear accumulation. However, we demonstrate that WTIP is recruited to nephrin, upon nephrin tyrosine phosphorylation by Src Family Kinases, in an Nck-dependent manner. WTIP is an evolutionarily conserved negative regulator of the Hippo kinase pathway, which inhibits the transcription factor Yap. Yap activity promotes podocyte survival. We show in mice that cannot recruit Nck to nephrin, and by extension WTIP, that Yap protein levels are downregulated.
    [Show full text]
  • SHOC2–MRAS–PP1 Complex Positively Regulates RAF Activity and Contributes to Noonan Syndrome Pathogenesis
    SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis Lucy C. Younga,1, Nicole Hartiga,2, Isabel Boned del Ríoa, Sibel Saria, Benjamin Ringham-Terrya, Joshua R. Wainwrighta, Greg G. Jonesa, Frank McCormickb,3, and Pablo Rodriguez-Vicianaa,3 aUniversity College London Cancer Institute, University College London, London WC1E 6DD, United Kingdom; and bHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158 Contributed by Frank McCormick, September 18, 2018 (sent for review November 22, 2017; reviewed by Deborah K. Morrison and Marc Therrien) Dephosphorylation of the inhibitory “S259” site on RAF kinases CRAF/RAF1 mutations are also frequently found in NS and (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. cluster around the S259 14-3-3 binding site, enhancing CRAF ac- The MRAS GTPase, a close relative of RAS oncoproteins, interacts tivity through disruption of 14-3-3 binding (8) and highlighting the with SHOC2 and protein phosphatase 1 (PP1) to form a heterotri- key role of this regulatory step in RAF–ERK pathway activation. meric holoenzyme that dephosphorylates this S259 RAF site. MRAS is a very close relative of the classical RAS oncoproteins MRAS and SHOC2 function as PP1 regulatory subunits providing (H-, N-, and KRAS, hereafter referred to collectively as “RAS”) the complex with striking specificity against RAF. MRAS also func- and shares most regulatory and effector interactions as well as tions as a targeting subunit as membrane localization is required transforming ability (9–11). However, MRAS also has specific for efficient RAF dephosphorylation and ERK pathway regulation functions of its own, and uniquely among RAS family GTPases, it in cells.
    [Show full text]
  • The Human Genome Project
    TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 Contents FOREWORD . 2 THE GENOME PROJECT—WHY THE DOE? . 4 A bold but logical step INTRODUCING THE HUMAN GENOME . 6 The recipe for life Some definitions . 6 A plan of action . 8 EXPLORING THE GENOMIC LANDSCAPE . 10 Mapping the terrain Two giant steps: Chromosomes 16 and 19 . 12 Getting down to details: Sequencing the genome . 16 Shotguns and transposons . 20 How good is good enough? . 26 Sidebar: Tools of the Trade . 17 Sidebar: The Mighty Mouse . 24 BEYOND BIOLOGY . 27 Instrumentation and informatics Smaller is better—And other developments . 27 Dealing with the data . 30 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS . 32 An essential dimension of genome research Foreword T THE END OF THE ROAD in Little has been rapid, and it is now generally agreed Cottonwood Canyon, near Salt that this international project will produce Lake City, Alta is a place of the complete sequence of the human genome near-mythic renown among by the year 2005. A skiers. In time it may well And what is more important, the value assume similar status among molecular of the project also appears beyond doubt. geneticists. In December 1984, a conference Genome research is revolutionizing biology there, co-sponsored by the U.S. Department and biotechnology, and providing a vital of Energy, pondered a single question: Does thrust to the increasingly broad scope of the modern DNA research offer a way of detect- biological sciences.
    [Show full text]
  • Alterations of the Interactome of Bcl-2 Proteins in Breast Cancer at the Transcriptional, Mutational and Structural Level
    RESEARCH ARTICLE Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, 1,2 Elena PapaleoID * 1 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark, a1111111111 2 Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 Abstract Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B- OPEN ACCESS cell lymphoma-2 (Bcl-2) family regulate programmed cell death by the mitochondrial apopto- sis pathway. In response to intracellular stress, the apoptotic balance is governed by inter- Citation: Kønig SM, Rissler V, Terkelsen T, Lambrughi M, Papaleo E (2019) Alterations of the actions of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology interactome of Bcl-2 proteins in breast cancer at 3)-only proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in the transcriptional, mutational and structural level. expression levels, stability, and functional impairment of pro-survival proteins can lead to an PLoS Comput Biol 15(12): e1007485. https://doi. imbalance in tissue homeostasis. Their overexpression or hyperactivation can result in org/10.1371/journal.pcbi.1007485 oncogenic effects. Pro-survival Bcl-2 family members carry out their function by binding the Editor: Igor N. Berezovsky, A�STAR Singapore, BH3 short linear motif of pro-apoptotic proteins in a modular way, creating a complex net- SINGAPORE work of protein-protein interactions. Their dysfunction enables cancer cells to evade cell Received: July 8, 2019 death.
    [Show full text]
  • Alterations of the Interactome of Bcl-2 Proteins in Breast Cancer at the Transcriptional, Mutational and Structural Level
    Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level Konig, Simon Mathis; Rissler, Vendela; Terkelsen, Thilde; Lambrughi, Matteo; Papaleo, Elena Published in: P L o S One DOI: 10.1371/journal.pcbi.1007485 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Konig, S. M., Rissler, V., Terkelsen, T., Lambrughi, M., & Papaleo, E. (2019). Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level. P L o S One, 15(12), [e1007485]. https://doi.org/10.1371/journal.pcbi.1007485 Download date: 25. sep.. 2021 RESEARCH ARTICLE Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, 1,2 Elena PapaleoID * 1 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark, a1111111111 2 Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 Abstract Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B- OPEN ACCESS cell lymphoma-2 (Bcl-2) family regulate programmed cell death by the mitochondrial apopto- sis pathway. In response to intracellular stress, the apoptotic balance is governed by inter- Citation: Kønig SM, Rissler V, Terkelsen T, Lambrughi M, Papaleo E (2019) Alterations of the actions of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology interactome of Bcl-2 proteins in breast cancer at 3)-only proteins, the pro-survival, and the pro-apoptotic executioner proteins.
    [Show full text]
  • Human RRAS (1-215, His-Tag) - Purified
    OriGene Technologies, Inc. OriGene Technologies GmbH 9620 Medical Center Drive, Ste 200 Schillerstr. 5 Rockville, MD 20850 32052 Herford UNITED STATES GERMANY Phone: +1-888-267-4436 Phone: +49-5221-34606-0 Fax: +1-301-340-8606 Fax: +49-5221-34606-11 [email protected] [email protected] AR09434PU-L Human RRAS (1-215, His-tag) - Purified Alternate names: R-Ras, Ras-related protein R-Ras Quantity: 0.25 mg Concentration: 0.5 mg/ml (determined by Bradford assay) Background: RRAS, also known as ras-related protein R-Ras, belongs to the Ras family which functions in signal transduction pathways. This protein has been shown to interact with RASSF5, NCK1, Bcl-2, ARAF and RALGDS. RRAS can bind GTP and GDP, and it has intrinsic GTPase activity. It also regulates the organization of the actin cytoskeleton. Uniprot ID: P10301 NCBI: NP_006261 GeneID: 6237 Species: Human Source: E. coli Format: State: Liquid purified protein Purity: >85% by SDS - PAGE Buffer System: 20 mM Tris-HCl buffer (pH 8.0) containing 10% glycerol, 0.1 M NaCl Description: Recombinant RRAS protein, fused to His-tag at N-terminus, was expressed in E.coli and purified by using conventional chromatography techniques. AA Sequence: MGSSHHHHHH SSGLVPRGSH MSSGAASGTG RGRPRGGGPG PGDPPPSETH KLVVVGGGGV GKSALTIQFI QSYFVSDYDP TIEDSYTKIC SVDGIPARLD ILDTAGQEEF GAMREQYMRA GHGFLLVFAI NDRQSFNEVG KLFTQILRVK DRDDFPVVLV GNKADLESQR QVPRSEASAF GASHHVAYFE ASAKLRLNVD EAFEQLVRAV RKYQEQELPP SPPSAPRKKG GGCPC Molecular weight: 25.3 kDa (235 aa), confirmed by MALDI-TOF Storage: Store undiluted at 2-8°C for up to two weeks or (in aliquots) at -20°C or -70°C for longer. Avoid repeated freezing and thawing.
    [Show full text]
  • Connecting Myelin-Related and Synaptic Dysfunction In
    www.nature.com/scientificreports OPEN Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich Received: 24 October 2016 Accepted: 27 February 2017 gene expression hubs Published: 07 April 2017 Hedi Hegyi Combining genome-wide mapping of SNP-rich regions in schizophrenics and gene expression data in all brain compartments across the human life span revealed that genes with promoters most frequently mutated in schizophrenia are expression hubs interacting with far more genes than the rest of the genome. We summed up the differentially methylated “expression neighbors” of genes that fall into one of 108 distinct schizophrenia-associated loci with high number of SNPs. Surprisingly, the number of expression neighbors of the genes in these loci were 35 times higher for the positively correlating genes (32 times higher for the negatively correlating ones) than for the rest of the ~16000 genes. While the genes in the 108 loci have little known impact in schizophrenia, we identified many more known schizophrenia-related important genes with a high degree of connectedness (e.g. MOBP, SYNGR1 and DGCR6), validating our approach. Both the most connected positive and negative hubs affected synapse-related genes the most, supporting the synaptic origin of schizophrenia. At least half of the top genes in both the correlating and anti-correlating categories are cancer-related, including oncogenes (RRAS and ALDOA), providing further insight into the observed inverse relationship between the two diseases. Gene expression correlation, protein-protein interaction and other high-throughput experiments in the post-genomic era have revealed that genes tend to form complex, scale-free networks where most genes have a few connections with others and a few have a high number of interactions, commonly referred to as “hubs”, estab- lishing them as important central genes in these gene networks1.
    [Show full text]
  • The Human Gene Connectome As a Map of Short Cuts for Morbid Allele Discovery
    The human gene connectome as a map of short cuts for morbid allele discovery Yuval Itana,1, Shen-Ying Zhanga,b, Guillaume Vogta,b, Avinash Abhyankara, Melina Hermana, Patrick Nitschkec, Dror Friedd, Lluis Quintana-Murcie, Laurent Abela,b, and Jean-Laurent Casanovaa,b,f aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris Descartes University, Institut National de la Santé et de la Recherche Médicale U980, Necker Medical School, 75015 Paris, France; cPlateforme Bioinformatique, Université Paris Descartes, 75116 Paris, France; dDepartment of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; eUnit of Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Institut Pasteur, F-75015 Paris, France; and fPediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France Edited* by Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 15, 2013 (received for review October 19, 2012) High-throughput genomic data reveal thousands of gene variants to detect a single mutated gene, with the other polymorphic genes per patient, and it is often difficult to determine which of these being of less interest. This goes some way to explaining why, variants underlies disease in a given individual. However, at the despite the abundance of NGS data, the discovery of disease- population level, there may be some degree of phenotypic homo- causing alleles from such data remains somewhat limited. geneity, with alterations of specific physiological pathways under- We developed the human gene connectome (HGC) to over- come this problem.
    [Show full text]
  • Identification of RRAS Gene Related to Nasopharyngeal Carcinoma Based on Pathway and Network-Based Analyses
    675 Original Article Identification of RRAS gene related to nasopharyngeal carcinoma based on pathway and network-based analyses Ruowen Xiao1#, Lu Shi2#, Te Yang3, Meiyin Zhang1, Huiyun Wang1, Shijuan Mai1 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; 2Department of Thoracic Oncology, the Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China; 3Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China Contributions: (I) Conception and design: S Mai, H Wang; (II) Administrative support: S Mai, H Wang, M Zhang; (III) Provision of study materials or patients: R Xiao, L Shi, T Yang; (IV) Collection and assembly of data: R Xiao, L Shi; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Professor Shijuan Mai; Professor Huiyun Wang. Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou 510060, China. Email: [email protected]; [email protected]. Background: Nasopharyngeal carcinoma (NPC) is a highly aggressive neoplasm mainly distributed in the eastern and southeastern parts of Asia. NPC has a poor prognosis among head and neck cancers, and molecular-targeted therapies showed limited clinical efficacy. Methods: We reviewed publications in the PubMed database and extracted genes associated with NPC.
    [Show full text]
  • Alterations of the Pro-Survival Bcl-2 Protein Interactome in Breast Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/695379; this version posted July 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Alterations of the pro-survival Bcl-2 protein interactome in 2 breast cancer at the transcriptional, mutational and 3 structural level 4 5 Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, Elena 6 Papaleo1,2 * 7 1Computational Biology Laboratory, Danish Cancer Society Research Center, 8 Strandboulevarden 49, 2100, Copenhagen 9 10 2Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo 11 Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, 12 Denmark 13 14 Abstract 15 16 Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B-cell 17 lymphoma-2 (Bcl-2) family regulates programmed cell death by the mitochondrial apoptosis 18 pathway. In response to intracellular stresses, the apoptotic balance is governed by interactions 19 of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology 3)-only 20 proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in expression 21 levels, stability, and functional impairment of pro-survival proteins can lead to an imbalance 22 in tissue homeostasis. Their overexpression or hyperactivation can result in oncogenic effects. 23 Pro-survival Bcl-2 family members carry out their function by binding the BH3 short linear 24 motif of pro-apoptotic proteins in a modular way, creating a complex network of protein- 25 protein interactions.
    [Show full text]
  • Comparative Genomic Hybridization Indicating Two Distinct Subgroups of Pilocytic Astrocytomas
    Neurosurg Focus 8 (4):Clinical Pearl 2, 2000, Click here to return to Table of Contents Comparative genomic hybridization indicating two distinct subgroups of pilocytic astrocytomas JANUSZ SZYMAS, M.D., PH.D., GUNTHER WOLF, PH.D., SIMONE PETERSEN, PH.D., KARSTEN SCHLUENS, PH.D., STANISLAW NOWAK, M.D., PH.D., AND IVER PETERSEN, M.D., PH.D. Departments of Pathology and Neurosurgery, University of Medical Sciences, Poznan, Poland; and Institute of Pathology, University-Hospital Charite, Berlin, Germany Object. The authors investigated the spectrum of chromosomal imbalances of pilocytic astrocytoma by using com- parative genomic hybridization (CGH). Methods. Tumor DNA was extracted from surgically obtained samples of 18 pilocytic astrocytomas that were exam- ined for the presence of neoplastic tissue on frozen sections. Comparative genomic hybridization was performed using standard procedures, and digital image analysis was conducted using out by custom-made software. The chromosomal alterations were determined by a statistical procedure in which Student's t-test (99% confidence interval) was used. Details on CGH analysis and individual ratio profiles are available at http://amba.charite.de/cgh/. Conclusions. The results suggests the presence of two distinct genetic subgroups of pilocytic astrocytoma, with imbalances of chromosome 19 being the major change for differentiation. In the first group (10 samples), deletions on chromosome 19 were shown as well as multiple gains mainly on chromosomes 5 and 6q but also on chromosomes 4, 7, 8, 10, and 11. The second group (eight samples) was characterized by overrepresentation on chromosomes 19p and 22q, which were associated with deletions on 4q, 5q, 6q, 9p, 13q, and 18q.
    [Show full text]
  • R-Ras Gtpases Signaling Role in Myelin Neurodegenerative Diseases
    International Journal of Molecular Sciences Review R-Ras GTPases Signaling Role in Myelin Neurodegenerative Diseases Berta Alcover-Sanchez , Gonzalo Garcia-Martin , Francisco Wandosell and Beatriz Cubelos * Departamento de Biología Molecular and Centro Biología Molecular “Severo Ochoa”, Universidad Autónoma de Madrid, 28049 Madrid, Spain; [email protected] (B.A.-S.); [email protected] (G.G.-M.); [email protected] (F.W.) * Correspondence: [email protected]; Tel.: +34-91-1964561 Received: 23 July 2020; Accepted: 14 August 2020; Published: 17 August 2020 Abstract: Myelination is required for fast and efficient synaptic transmission in vertebrates. In the central nervous system, oligodendrocytes are responsible for creating myelin sheaths that isolate and protect axons, even throughout adulthood. However, when myelin is lost, the failure of remyelination mechanisms can cause neurodegenerative myelin-associated pathologies. From oligodendrocyte progenitor cells to mature myelinating oligodendrocytes, myelination is a highly complex process that involves many elements of cellular signaling, yet many of the mechanisms that coordinate it, remain unknown. In this review, we will focus on the three major pathways involved in myelination (PI3K/Akt/mTOR, ERK1/2-MAPK, and Wnt/β-catenin) and recent advances describing the crosstalk elements which help to regulate them. In addition, we will review the tight relation between Ras GTPases and myelination processes and discuss its potential as novel elements of crosstalk between the pathways. A better understanding of the crosstalk elements orchestrating myelination mechanisms is essential to identify new potential targets to mitigate neurodegeneration. Keywords: myelin; oligodendrocyte; neurodegeneration; PI3K/Akt/mTOR; ERK1/2-MAPK; Wnt/β-catenin; R-Ras 1.
    [Show full text]